Red cells, hemoglobin, heme, iron, and atherogenesis.

OBJECTIVE: We investigated whether red cell infiltration of atheromatous lesions promotes the later stages of atherosclerosis. METHODS AND RESULTS: We find that oxidation of ferro (FeII) hemoglobin in ruptured advanced lesions occurs generating ferri (FeIII) hemoglobin and via more extensive oxidation ferrylhemoglobin (FeIII/FeIV=O). The protein oxidation marker dityrosine accumulates in complicated lesions, accompanied by the formation of cross-linked hemoglobin, a hallmark of ferrylhemoglobin. Exposure of normal red cells to lipids derived from atheromatous lesions causes hemolysis and oxidation of liberated hemoglobin. In the interactions between hemoglobin and atheroma lipids, hemoglobin and heme promote further lipid oxidation and subsequently endothelial reactions such as upregulation of heme oxygenase-1 and cytotoxicity to endothelium. Oxidative scission of heme leads to release of iron and a feed-forward process of iron-driven plaque lipid oxidation. The inhibition of heme release from globin by haptoglobin and sequestration of heme by hemopexin suppress hemoglobin-mediated oxidation of lipids of atheromatous lesions and attenuate endothelial cytotoxicity. CONCLUSIONS: The interior of advanced atheromatous lesions is a prooxidant environment in which erythrocytes lyse, hemoglobin is oxidized to ferri- and ferrylhemoglobin, and released heme and iron promote further oxidation of lipids. These events amplify the endothelial cell cytotoxicity of plaque components.

In vitro study of the effect of anti-hypertensive medication with anti-oxidant side effect on the chemiluminescence of peripheral blood phagocytes in patients with hypertension and healthy individuals / Egyes, antioxidáns mellékhatású "vérnyomás"gyógyszerek hatása magas vérnyomásban szenvedo és egészséges személyek vérsejtjeinek fagocitakemilumineszcenciájára in vitro.

Összefoglaló. Bevezetés: Az atorvasztatin (koleszterincsökkento), nifedipin (Ca2+-antagonista), kaptopril (angiotenzinkonvertáz-gátló) vegyületek a magas vérnyomás komplex kezelésének "alap"gyógyszerei. Mindhárom antioxidáns is. Célkituzés: A tanulmány célja annak megválaszolása volt, hogy e molekulák gátolhatják-e a vérsejtek fagocitamuködését. Betegek és módszer: Magas vérnyomásos betegek: 15 fo, 39-80 éves, no: 6, férfi: 9. Egészséges kontroll: 7 fo, 30-75 éves, no: 3, férfi: 4. A vizsgálat a téli hónapokban zajlott. A zimozán- (Saccharomyces cerevisiae) részecskék fagocitózisa során képzodo kemilumineszcencia mérése perifériás vérben a gyógyszerek jelenlétében történt luminométerrel. A gátlást a stimulációs index értékének csökkenésével jellemeztük. Eredmények: Mindhárom vegyület gátolta a kemilumineszcenciát (oxigénszabadgyök-képzést) a 65 év feletti, magas vérnyomásos betegek többségében: 11/13 fonél. Foleg magasabb életkorban és cukorbetegségben, de más társbetegségekben nott a gátlás. Következtetés: Az idos, magas vérnyomásos betegek fokozott orvosi figyelmet igényelnek a téli idoszakokban, mivel antioxidáns hatással is rendelkezo "alap"gyógyszereiknek, egyéntol függoen, lehetnek gátló hatásaik a fagociták mikrobaölo, oxigénszabadgyök-termelo képességére. Orv Hetil. 2020; 161(45): 1908-1913. INTRODUCTION: Atorvastatin (cholesterol synthesis blocker), nifedipine (Ca2+ antagonist), captopril (angiotensin-convertase inhibitor) are basic drugs in the therapy of hypertension. They are also antioxidants. OBJECTIVE: To investigate whether these molecules can inhibit the phagocytic activity of peripheral blood cells. PATIENTS AND METHOD: Hypertension group: 15 patients with ages between 39-80 years (6 women and 9 men). Healthy control group: 7 individuals with ages between 30-75 years (3 women and 4 men). The study was carried out in wintertime. The measurement of phagocytic activity was carried out by luminometry in peripheral blood samples. Chemiluminescence intensities were determined by the engulfment of zymosan (Saccharomyces cerevisiae) particles in the presence of drugs. The inhibitory effects were characterized by the decreased values of the stimulation index. RESULTS: All three substances decreased the chemiluminescence (reactive oxygen species production) in the majority of samples from hypertensive patients over 65 years: in 11 of 13 patients. Stronger inhibition was detected in older, diabetic patients with other co-morbidities, too. CONCLUSION: Older patients with hypertension require a special attention in wintertime. Antihypertensive drugs with antioxidant capabilities may have individually different inhibitory effects on the production of reactive oxygen species by phagocytes, which decreases their antimicrobial potency. Orv Hetil. 2020; 161(45): 1908-1913.

Effect of antithyroid drugs on the occurrence of antibodies against type 2 deiodinase (DIO2), which are involved in hyperthyroid Graves' disease influencing the therapeutic efficacy.

Graves' disease is an organ-specific autoimmune disease with hyperthyroidism, diffuse goiter and autoantibodies against TSH receptor, thyroid peroxidase (TPO) and/or thyroglobulin (Tg). Graves' hyperthyroidism is characterized by T3 dominance due to the conversion of T4 into T3 through type 1 and 2 deiodinase enzymes (DIO1, DIO2). Methimazole (MMI) and propylthiouracil (PTU) therapies inhibit thyroid hormone synthesis blocking the activity of deiodinase and TPO enzymes. The study investigated the occurrence of autoantibodies against DIO2 peptides (cys- and hom-peptides) with the effect of antithyroid drugs on their frequencies in 78 patients with Graves' disease and 30 controls. In hyperthyroidism, the presence of DIO2 peptide antibodies was as follows: 20 and 11 cases out of 51 for cys- and hom-peptide antibodies, respectively, of whom 8 cases possessed antibodies against both peptides. Antithyroid drugs differently influenced their frequencies, which were greater in PTU than in MMI (3/6 vs 13/45 cases, P < 0.016 for cys- and 0/6 vs 2/45 cases for hom-peptide antibodies). Antibodies against both peptides demonstrated more reduced levels of anti-TPO (P < 0.003) and anti-Tg antibodies (P < 0.002) compared with those without peptide antibodies. PTU compared with MMI increased the levels of TSH receptor antibodies (32.5 UI/l vs 2.68 IU/l, P < 0.009). MMI treatment led to more reduced FT3 levels and FT3/FT4 ratios in hyperthyroid Graves' ophthalmopathy (P < 0.028 for FT3, P < 0.007 for FT3/FT4 ratio). In conclusion, the presence of DIO2 peptide antibodies is connected to Graves' hyperthyroidism influencing the levels of antibodies against TPO, Tg and TSH receptor, as well as the therapeutic efficacy of antithyroid drugs.

Hyperthyroidism in Patients with Graves' Ophthalmopathy, and Thyroidal, Skeletal and Eye Muscle Specific Type 2 Deiodinase Enzyme Activities.

Graves' ophthalmopathy is characterized by hyperthyroidism, which is associated with higher serum T3 levels than T4 due to deiodinase enzymes.The effect of Graves' patient's sera (n=52) with elevated thyroid hormone and TSH receptor or thyroid peroxidase antibody (anti-TPO) levels was investigated on thyroidal, skeletal and eye muscle type 2 deiodinase enzyme (DII) activities. DII activities were measured with 125I-T4 substrate, while thyroid hormone and antibody levels with immunoassays.In Graves' ophthalmopathy, sera with elevated FT4 or FT3 levels reduced DII activites remarkably in all tissue fractions. Thyroidal DII activities were lower than those using eye muscle fraction (0.6±0.22 vs 1.14±0.43 pmol/mg/min, P<0.006). Effect of sera with increased FT3 levels demonstrated also reduced DII activities in patients with Graves' ophthalmopathy after methimazole therapy compared to those who had no ophthalmopathy (2.88±2 vs 20.42±11.82 pmol/mg/min, P<0.006 for thyroidal fraction, 4.07±2.72 vs 29.22±15.46 pmol/mg/min, P<0.004 for skeletal muscle, 5.3±3.47 vs 37.87±18.82 pmol/mg/min, P<0.003 for eye muscle). Hyperthyroid sera with TSH receptor antibodies resulted in increased DII activities, while sera with anti-TPO antibodies were connected to lower DII activities in Graves' ophthalmopathy.In summary, the actions of hyperthyroid sera derived from patients with Graves' disease were tested on tissue-specific DII activities. Elevated FT4 level-induced DII inactivation is present in Graves' ophthalmopathy, which seems to be also present at the beginning of methimazole therapy. Stimulating TSH receptor antibiodies increased DII activities via their nongenomic effects using sera of hyperthyroid Graves' ophthalmopathy, but anti-TPO antibodies could influence DII activities via altering FT4 levels.

Differences in angiotensin convertase enzyme (ACE) activity and expression may contribute to shorter event free period after coronary artery bypass graft surgery.

AIMS: The goal of this study was to investigate the importance of the vascular angiotensin convertase enzyme (ACE) in coronary artery bypass graft surgery (CABG) patients. METHODS: Vascular tissue (distal saphenous vein [n= 163] and/or radial artery [n= 120] segments) and blood samples were collected from CABG patients (n= 81). We studied (i) the potency of angiotensin I (AngI) and angiotensin II (AngII) to evoke vascular contractions; (ii) vascular and plasma ACE concentrations; and (iii) ACE genotype of the patients enrolled. RESULTS: The ratio of the potencies (EC(50) ) of AngII and AngI was significantly lower in radial artery compared to the saphenous vein (0.17 ± 0.03 nM and 0.51 ± 0.14 nM, respectively, P= 0.003), suggesting a 3-fold more effective AngI conversion in saphenous vein samples. Angiotensin constrictions were inhibited with telmisartan and captopril in both saphenous veins and radial arteries. Vascular ACE expression was significantly higher in saphenous vein compared to radial artery (9.7 ± 1.0 ng/mg and 5.3 ± 0.7 ng/mg, respectively, P= 0.01). Serum but no tissue ACE concentration was determined by ACE insertion/deletion polymorphism. Accordingly, no relation was found between serum and tissue ACE expression. CONCLUSION: ACE-inhibitor therapy targeting tissue located ACE may be beneficial to patients with saphenous vein grafts after CABG surgery.